Background Chronic musculoskeletal pain conditions are among the most common problems seen in primary care. As the importance of these conditions for the health of individuals and society has been increasingly recognized, use of long-term opioid therapy for chronic musculoskeletal pain has grown exponentially. Unfortunately, research has not kept pace with this change in prescribing practice. Although evidence supports the ability of opioid analgesics to produce short-term reductions in pain intensity, long-term trials evaluating opioid effectiveness are not available. Evidence for effects of opioids on function and quality of life ar limited, but observational data indicate that many patients treated with long-term opioids continue to experience severe pain and functional limitations. Furthermore, the long-term safety of opioids is poorly described in the literature. Preliminary investigations suggest that opioid therapy may adversely affect pain sensitivity, endocrine function, fall risk, and sleep, but the incidence and severity of these potential effects have not been well-quantified. Additionally, although opioid misuse and addiction have been the focus of substantial attention, estimates of their prevalence are based on research with important limitations. Objectives The main objective of the Strategies for Prescribing Analgesics Comparative Effectiveness (SPACE) Trial are to compare two prescribing strategies: 1) an opioid-intensive strategy that uses strong opioids, such as morphine, early in treatment, and 2) an opioid-avoidant strategy that optimizes non-opioid medications while delaying and minimizing opioid use. SPACE will evaluate, over 12 months, 1) the effects of opioid-intensive versus opioid-avoidant prescribing strategies on pain-related function and pain intensity and 2) the adverse effects of opioid-intensive versus opioid-avoidant prescribing strategies. Secondarily, we will examine effects of the two prescribing strategies on health-related quality of life, pain sensitivity, and aberrant drug-related behaviors We will also conduct a secondary qualitative analysis to better understand patients' perceptions of their response to the intervention and of the value of intervention components. Methods SPACE is a pragmatic randomized clinical trial designed to compare the effectiveness and safety over 12 months of two clinically-relevant prescribing strategies for chronic musculoskeletal pain. Eligible Veterans will be those seen in primary care for chronic back or lower-extremity arthritis pain who have moderate-severe pain intensity and interference with function despite daily analgesics. Those currently receiving chronic daily opioid therapy will be excluded. Participants will be randomized to the opioid-intensive (n=138) or the opioid-avoidant (n=138) arm, with stratification by primary pain location (back or hip/knee). Medications in each arm will be adjusted to target improvement in pain, while considering individual patient preferences and responses. Interventions will be delivered in a care management model using the assigned prescribing strategies, automated symptom monitoring, and a structured decision-making approach to guide medication adjustment. Outcome assessors masked to treatment assignment will conduct interviews to assess patient-reported outcomes at 0, 3, 6, 9, and 12 months and will assess pain sensitivity, physical performance, and cognitive function at 0, 6, and 12 months. For the primary outcome, the Brief Pain Inventory (BPI) Interference scale, the study will have 80% power to detect a 1 point difference between groups, assuming 2-sided alpha=0.05 and 20% attrition. Analysis will use an intent-to-treat approach, including all participants in the arm to which they were originally assigned.